The prognosis of patients with pancreatic cancer is extremely poor, with 5-yr survival rates lower than 5%. While the reasons for this biological aggressiveness have not been clearly elucidated, the impact of the extensive tumor stroma and desmoplastic reaction, both of which are unique features of pancreatic cancer, have been implicated in the promotion of tumor progression and metastasis. Although several studies have utilized receptor targeted nanoparticles for improved detection and treatment of pancreatic cancer with generally poor success, the use of multifunctional nanoparticles targeted to the stroma, which can comprise up to 80% of the total tumor volume, could result in a game-changing outcome. To actively target the tumor stroma of pancreatic cancer, our objective is to develop a dual stroma targeted multifunctional theranostic nanoparticle which will facilitate improved detection of pancreatic cancer and deliver a demethylating agent to result in a synergistic therapy upon combination with stereotactic body radiation. Building upon our successful targeting of pancreatic cancer using Syndecan-1, this proposal will develop and test a novel multimodal approach centered on the use of a stroma targeted nanoparticle (Syndecan-XT) which will serve as a tumor specific optoacoustic contrast agent and drug delivery vehicle for Decitabine, a hypomethylating agent. To improve tumor stroma targeting, we will utilize a dual approach using 1) Syndecan-1, which binds to the collagen IV and fibronectin matrix proteins as well as elevated tumor receptors, i.e. insulin growth-like factor 1 receptor (IGF1- R), and a 2) gelatin capped, colloidal mesoporous silica nanoparticle, which will facilitate drug release upon digestion of the gelatin by MMPs 2 and 9. We will test the overarching hypothesis that stroma-targeted Syndecan-XT nanoparticles encapsulating hypomethylating agents will significantly improve the detection of pancreatic tumors and efficacy of SBRT therapy to result in synergistic tumor kill while resulting in reduced off-target cytotoxicity. We will test this hypothesis using the following aims: Aim 1) Develop, characterize, optimize, and evaluate Syndecan-XT nanoparticles as theranostic-radiosenisitizing nanoparticles for specific targeting of the stroma of pancreatic tumors; Aim 2) Optimize regimen for Syndecan-XT nanoparticles and SBR radiation therapy in vivo; Aim 3) Assess therapeutic efficacy of SBR therapy and Syndecan-XT with or without Decitabine in combination with radiation therapy in orthotopic and KPC models of pancreatic cancer. Successful completion of these aims will provide a solid foundation for the ultimate goal of the proposed Syndecan- XT+SBR therapy which is the conversion of patients with unresectable pancreatic cancer to become candidates for surgical resection.